The devastating effects of drug addiction on the lives of those who struggle with it, and the social and economic implications for society as a whole are staggering. Faced with this challenge, understanding the biological pathways that predispose individuals to addiction to cocaine (and other drugs) is a top priority in the research community. Genetic background is thought to influence an individual's predisposition to abuse drugs and this hypothesis is supported by studies in animal models, by clinical observations in humans, and by animal studies showing mouse inbred strain differences in behaviors that model addiction liability. While no animal model exists that recapitulates the entire spectrum of the drug abuse syndrome in humans, animal models do exist to examine specific drug[unreadable]related behaviors. Locomotor response to drug administration models initial sensitivity to the stimulant effects of the drug. Rodents that exhibit increased locomotor response to psycho stimulants also show faster rates of acquisition in drug self[unreadable]administration assays, which suggests that initial sensitivity to cocaine predicts liability to addiction. The goal of this proposal is to identify genetic loci involved in the regulation of cocaine locomotor response as an indication of drug sensitivity. Our strategy takes advantage of naturally occurring phenotypic variation between inbred mouse strains and haplotype association mapping, a genetic approach for mapping complex trait genes. In addition, gene expression paHerns in brain regions involved in drug response and addiction as well as pharmacokinetic properties of cocaine will be examined across strains to identify gene expression and pharmacokinetic differences that may contribute to phenotypic variation.